ABSTRACT
Structure activity relationship (SAR) investigation of an oxadiazole based series led to the discovery of several potent FLAP inhibitors. Lead optimization focused on achieving functional activity while improving physiochemical properties and reducing hERG inhibition. Several compounds with favorable in vitro and in vivo properties were identified that were suitable for advanced profiling.
Subject(s)
5-Lipoxygenase-Activating Protein Inhibitors/chemistry , 5-Lipoxygenase-Activating Proteins/metabolism , Oxadiazoles/chemistry , 5-Lipoxygenase-Activating Protein Inhibitors/metabolism , 5-Lipoxygenase-Activating Proteins/chemistry , Animals , Drug Evaluation, Preclinical , ERG1 Potassium Channel/antagonists & inhibitors , ERG1 Potassium Channel/metabolism , Half-Life , Humans , Inhibitory Concentration 50 , Male , Microsomes, Liver/metabolism , Oxadiazoles/metabolism , Rats , Rats, Sprague-Dawley , Rats, Wistar , Solubility , Structure-Activity RelationshipABSTRACT
A practical sequence involving a noncryogenic stereospecific boronate rearrangement followed by a robust formylation with an in situ generated DCM anion has been developed for the asymmetric construction of an all-carbon quaternary stereogenic center of a FLAP inhibitor. The key boronate rearrangement was rendered noncryogenic and robust by using LDA as the base and instituting an in situ trapping of the unstable lithiated benzylic carbamate with the boronic ester. A similar strategy was implemented for the DCM formylation reaction. It was found that the 1,2-boronate rearrangement for the formylation reaction could be temperature-controlled, thus preventing overaddition of the DCM anion and rendering the process reproducible. The robust stereospecific boronate rearrangement and formylation were utilized for the practical asymmetric synthesis of a chiral quaternary FLAP inhibitor.
Subject(s)
5-Lipoxygenase-Activating Protein Inhibitors/chemical synthesis , Boron Compounds/chemistry , Carbamates/chemistry , 5-Lipoxygenase-Activating Protein Inhibitors/chemistry , Catalysis , Molecular Structure , StereoisomerismABSTRACT
A new class of chymase inhibitor featuring a benzimidazolone core with an acid side chain and a P(1) hydrophobic moiety is described. Incubation of the lead compound with GSH resulted in the formation of a GSH conjugate on the benzothiophene P(1) moiety. Replacement of the benzothiophene with different heterocyclic systems such as indoles and benzoisothiazole is feasible. Among the P(1) replacements, benzoisothiazole prevents the formation of GSH conjugate and an in silico analysis of oxidative potentials agreed with the experimental outcome.
Subject(s)
Benzimidazoles/chemistry , Chymases/antagonists & inhibitors , Protease Inhibitors/chemistry , Benzimidazoles/metabolism , Benzimidazoles/pharmacology , Binding Sites , Chymases/metabolism , Crystallography, X-Ray , Humans , Hydrophobic and Hydrophilic Interactions , Oxidation-Reduction , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Protein Structure, Tertiary , Structure-Activity RelationshipABSTRACT
An SAR study that identified a series of thienopyridine-based potent IkappaB Kinase beta (IKKbeta) inhibitors is described. With focuses on the structural optimization at C4 and C6 of structure 1 (Fig. 1), the study reveals that small alkyl and certain aromatic groups are preferred at C4, whereas polar groups with proper orientation at C6 efficiently enhance compound potency. The most potent analogues inhibit IKKbeta with IC50s as low as 40 nM, suppress LPS-induced TNF-alpha production in vitro and in vivo, display good kinase selectivity profiles, and are active in a HeLa cell NF-kappaB reporter gene assay, demonstrating that they directly interfere with the NF-kappaB signaling pathway.
Subject(s)
I-kappa B Kinase/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Pyridines/chemistry , Animals , Drug Discovery , HeLa Cells , Humans , I-kappa B Kinase/metabolism , Lipopolysaccharides/pharmacology , Mice , NF-kappa B/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Signal Transduction , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Interleukin-2 inducible T-cell kinase (ITK) is a member of the Tec kinase family and is involved with T-cell activation and proliferation. Due to its critical role in acting as a modulator of T-cells, ITK inhibitors could provide a novel route to anti-inflammatory therapy. This work describes the discovery of ITK inhibitors through structure-based design where high-resolution crystal structural information was used to optimize interactions within the kinase specificity pocket of the enzyme to improve both potency and selectivity.
Subject(s)
Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/metabolism , Amino Acid Motifs , Anti-Inflammatory Agents/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Crystallography, X-Ray/methods , Drug Design , Enzyme Inhibitors/chemical synthesis , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
A series of novel potent benzimidazole based inhibitors of interleukin-2 T-cell kinase (Itk) were prepared. In this report, we discuss the structure-activity relationship (SAR), selectivity, and cell-based activity for the series. We also discuss the SAR associated with an X-ray structure of one of the small-molecule inhibitors bound to ITK.
Subject(s)
Amides/chemistry , Benzimidazoles/chemistry , Carboxylic Acids/chemistry , Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/chemical synthesis , Microsomes, Liver/metabolism , Protein-Tyrosine Kinases/chemistry , Animals , Benzimidazoles/chemical synthesis , Carboxylic Acids/chemical synthesis , Crystallography, X-Ray , Drug Design , Enzyme Inhibitors/pharmacology , Inhibitory Concentration 50 , Mice , Models, Chemical , Molecular Conformation , Structure-Activity RelationshipABSTRACT
A series of novel 12-membered ring macrolides was designed based on available information on structure-activity relationships and macrolide-ribosome interactions. Compounds with the desosamine and the anchor group properly attached to the 12-membered lactone ring exhibited improved activity against erythromycin-resistant organisms.